Novartis AG

Patent Trials and Appeals Board

Oct 5, 2020

IPR2016-01479 (P.T.A.B. Oct. 5, 2020)

Trials@uspto.gov Paper 61
571-272-7822 Date: October 5, 2020

UNITED STATES PATENT AND TRADEMARK OFFICE

BEFORE THE PATENT TRIAL AND APPEAL BOARD

ARGENTUM PHARMACEUTICAL LLC,
Petitioner,
v.
NOVARTIS AG,
Patent Owner.

IPR2016-014791
Patent 9,006,224 B2

Before CHRISTOPHER L. CRUMBLEY, ROBERT A. POLLOCK, and
KRISTI L. R. SAWERT, Administrative Patent Judges.
CRUMBLEY, Administrative Patent Judge.

JUDGMENT
Final Written Decision
Determining No Challenged Claims Unpatentable
35 U.S.C. § 318(a)

1 This proceeding as initially filed named Par Pharmaceutical, Inc. as the
sole Petitioner. Argentum Pharmaceutical LLC was joined as a party to this
proceeding via a Motion for Joinder in IPR2017-01063; West-Ward
Pharmaceuticals International Limited was joined as a party via a Motion for
Joinder in IPR2017-01078. Subsequently, Par and West-Ward separately
requested termination of their participation in the proceeding pursuant to
settlement. Argentum Pharmaceutical LLC is the sole remaining Petitioner.
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I. INTRODUCTION
In this inter partes review, instituted pursuant to 35 U.S.C. § 314,
Argentum Pharmaceutical LLC (“Argentum”) challenges the patentability of
claims 1–3 of U.S. Patent No. 9,006,224 B2 (Ex. 1001, “the ’224 patent”),
owned by Novartis AG (“Novartis”).
We have jurisdiction under 35 U.S.C. § 6. This Final Written
Decision, issued pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73,
addresses issues and arguments raised during trial. For the reasons
discussed below, we determine that Argentum has not shown by a
preponderance of the evidence that claims 1–3 of the ’224 patent are
unpatentable.
A. Procedural History
On July 22, 2016, Par Pharmaceutical, Inc. (“Par”) filed a Petition
requesting an inter partes review of claims 1–3 of the ’224 patent. Paper 1
(“Pet.”). Novartis filed a Preliminary Response. Paper 7. On February 14,
2017, we instituted an inter partes review of the challenged claims. Paper 8
(“Dec.”). Subsequent to institution, Argentum and West-Ward
Pharmaceuticals International Limited (“West-Ward”) filed separate
petitions and motions for joinder with the instant proceeding. IPR2017-
01063, Papers 1, 3; IPR2017-01078, Papers 1, 3. On September 25, 2017,
we granted both motions for joinder, joining Argentum and West-Ward as
petitioners to this inter partes review. Paper 33. As we noted at the time,
both Argentum and West-Ward stated that their petitions include the same
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grounds and arguments2 as those in the Par proceeding, and both parties rely
on the same evidence including the same expert witness testimony. Id. at 5.
Following institution, Novartis filed a Patent Owner Response (Paper
17, “PO Resp.”) and Argentum filed a Reply (Paper 21, “Reply”). We
granted Novartis authorization to file a Surreply (Paper 26, “Surreply”) to
address alleged new arguments made in Argentum’s Reply, and permitted
Argentum to file a short Response (Paper 29).
Argentum relies upon the declaration testimony of Dr. Mark J. Ratain
(Ex. 1003), and with its Reply submitted a Supplemental Declaration of
Dr. Ratain (Ex. 1119). Novartis took cross-examination of Dr. Ratain via
deposition following the submission of each declaration, and filed the
transcripts (Exs. 2040, 2111). Novartis filed observations on the cross-
examination of Dr. Ratain (Paper 34) and Argentum filed a response to the
observations (Paper 42).
Novartis relies upon the declaration testimony of Dr. Matthew H.
Kulke. Ex. 2041. Argentum took cross-examination of Dr. Kulke via
deposition and submitted the transcript. Ex. 1070.
Novartis filed a Motion to Exclude certain evidence submitted by
Argentum (Paper 35, “Mot. Exclude”), after which Argentum filed an
Opposition (Paper 41, “Opp. Exclude”) and Novartis filed a Reply (Paper
43, “Reply Exclude”).

2 For this reason, although we cite to Par’s Petition in this decision because it
is of record in this proceeding, we attribute all the contentions made therein
to Argentum as the sole remaining Petitioner.
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Oral argument was requested by both parties. Papers 31, 36.
Argument was heard on November 1, 2017, and a transcript has been
entered into the record. Paper 49 (“Tr.”).
On January 23, 2018, Par and Novartis filed a joint motion to
terminate Par as a petitioner due to settlement (Paper 50), which we granted
on February 6, 2018 (Paper 52).
On February 14, 2018, counsel for Argentum contacted the Board via
e-mail, requesting that the Board hold the Final Written Decision in
abeyance in order to facilitate ongoing settlement discussions with Novartis.
Ex. 3002. We notified the parties that, in light of the parties’ request and
because the proceedings involve joinder, pursuant to 35 U.S.C. § 316(a)(11)
and 37 C.F.R. § 42.100(c) we would adjust the time for issuing a Final
Written Decision. Counsel for West-Ward3 e-mailed a similar request on
February 15, 2018. Ex. 3003. West-Ward continued to provide updates to
the Board via e-mail to notify us that settlement negotiations were ongoing
and to request that we continue to hold this Decision in abeyance.
On October 2, 2020, West-Ward and Novartis jointly requested to
terminate West-Ward as a petitioner due to settlement (Paper 57), which we
granted (Paper 60). Argentum is the sole remaining Petitioner in this
proceeding.

3 West-Ward updated its Mandatory Notices on January 8, 2019, notifying
us that it changed its name to Hikma Pharmaceuticals International Limited.
IPR2017-01078, Paper 11. Because the majority of the filings in this case
were made prior to the name change, for clarity of this Decision we will
refer to the company using its prior name, West-Ward.
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B. Related Proceedings
Claims 1 and 2 of the ’224 patent were challenged by a different
petitioner in IPR2016-01461; the Board denied institution of trial in that
proceeding.
We are informed that the ’224 patent has been asserted in two patent
infringement actions in the United States District Court for the District of
Delaware: Novartis Pharm. Corp. et al. v. Roxane Labs., Inc., No. 15-474-
RGA, and Novartis Pharm. Corp. et al. v. Par Pharm., Inc., No. 15-475-
RGA. Pet. 3; Paper 4, 2–3.
While this inter partes review was pending, the District Court entered
a decision in the former case, finding no invalidity of claim 1 the ’224
patent, on December 14, 2017. Novartis Pharm. Corp. v. West-Ward
Pharm. Int’l Ltd., 287 F. Supp. 3d 505 (D. Del. 2017) (“District Court
Decision”). That decision also found that certain claims of a related patent,
U.S. Patent No. 8,410,131 (“the ’131 patent”) were not invalid. Id. West-
Ward appealed the District Court’s decision as to the ’131 patent to the
United States Court of Appeals for the Federal Circuit, but did not appeal the
District Court’s decision regarding the ’224 parent at issue here. On May
13, 2019, the Federal Circuit affirmed. Novartis Pharm. Corp. v. West-Ward
Pharm. Int’l Ltd., 923 F.3d 1051 (Fed. Cir. 2019) (“Federal Circuit
Decision”).
C. The ’224 Patent
The ’224 patent, titled “Neuroendocrine Tumor Treatment,” issued
April 14, 2015, from U.S. Patent Application No. 12/094,173. Ex. 1001,
codes (54), (45), (21). The patent describes treating neuroendocrine tumors
using mTOR (mammalian target of rapamycin) inhibitors, including
rapamycin and its derivatives. Id. at 1:2–5, 1:17–43. One specifically listed
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rapamycin derivative is 40-O-(2-hydroxyethyl)-rapamycin, also known as
everolimus. Id. at 1:46–47, 11:50–51.
The ’224 patent discloses that mTOR inhibitors have activity as
immunosuppressants, and have also been found useful for the treatment of
solid tumors, particularly advanced solid tumors, including pancreatic
neuroendocrine tumors (PNETs). Id. at 2:35–67. PNETs are particularly
lethal, having a 5-year patient survival rate of 55.3%; the ’224 patent states
that most such tumors are malignant at the time of diagnosis, and 60% or
more present with liver metastases. Id. at 3:1–10. The ’224 patent
concludes that there is an unmet need for treatment of PNETs in patients
whose disease has progressed following one or more courses of
chemotherapy. Id. at 3:9–12.
The ’224 patent describes a method of treatment using mTOR
inhibitors, specifically with everolimus (also called “compound A”). Id. at
11:66–67. The patent proposes a clinical study in which patients with
advanced PNETs are treated with 10 mg/day of everolimus after failure of
cytotoxic chemotherapy. Id. at 26:56–60.
D. The Challenged Claims
Claim 1 is independent and illustrative of the challenged claims:
1. A method for treating pancreatic neuroendocrine tumors,
comprising administering to a human subject in need thereof a
therapeutically effective amount of 40-O-(2-hydroxyethyl)-rapamycin
as a monotherapy and wherein the tumors are advanced tumors after
failure of cytotoxic chemotherapy.
Ex. 1001, 26:66–27:4. Claim 2 specifies a unit dose of 10 mg/day, and
claim 3 requires that the tumor be an islet cell tumor. Id. at 27:5–8.
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E. The Instituted Grounds
We instituted an inter partes review of all claims challenged in the
Petition on the following grounds of unpatentability, each alleging
obviousness of the claims under 35 U.S.C. § 103(a)4:
Claim(s)
Challenged References
1–3 Öberg 2004,5 Boulay 2004,6 and O’Donnell7
2 Öberg 2004, Boulay 2004, O’Donnell, and Tabernero8
1–3 Boulay 2004, O’Donnell, and Duran9

4 The relevant sections of the Leahy-Smith America Invents Act (“AIA”),
Pub. L. No. 112–29, took effect on March 16, 2013. Because the application
from which the ’224 patent issued was filed before that date, our citations to
Title 35 are to its pre-AIA version.
5 K. Öberg, Treatment of neuroendocrine tumors of the gastrointestinal
tract, 27 ONCOLOGIA 57 (2004) (Ex. 1027).
6 A. Boulay et al., Antitumor efficacy of intermittent treatment schedules
with the rapamycin derivative RAD001 correlates with Prolonged
Inactivation of Ribosomal Protein S6 Kinase 1 in Peripheral Blood
Mononuclear Cells, 64 CANCER RES. 252 (2004) (Ex. 1005).
7 A. O’Donnell et al., A phase I study of the oral mTOR inhibitor RAD001 as
a monotherapy to identify the optimal biologically effective dose using
toxicity, pharmacokinetic (PK) and pharmacodynamics (PD) endpoints in
patients with solid tumors, 22 PROC. AM. SOC’Y OF CLINICAL ONCOLOGY
200(803ab) (2003) (Ex. 1029).
8 J. Tabernero et al., A phase I study with tumor molecular
pharmacodynamics (MPD) evaluation of dose and schedule of the oral
mTOR-inhibitor Everolimus (RAD001) in patients (pts) with advanced solid
tumors, 23 J. CLINICAL ONCOLOGY 3007 (2005) (Ex. 1038).
9 I. Duran et al., A Phase II Trial of Temsirolimus in Metastatic
Neuroendocrine Carcinomas (NECs), 23 SUPPLEMENT TO J. CLINICAL
ONCOLOGY 3096 (2005) (Ex. 1011).
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Claim(s)
Challenged References
2 Boulay 2004, O’Donnell, Duran, and Tabernero

II. ANALYSIS
A. Legal Standards
To prevail in challenging Novartis’s claims, Argentum must
demonstrate by a preponderance of the evidence that the claims are
unpatentable. 35 U.S.C. § 316(e); 37 C.F.R. § 42.1(d). A claim is
unpatentable under 35 U.S.C. § 103(a) if the differences between the
claimed subject matter and the prior art are such that the subject matter, as a
whole, would have been obvious at the time of the invention to a person
having ordinary skill in the art. KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398,
406 (2007). The question of obviousness is resolved on the basis of
underlying factual determinations including: (1) the scope and content of
the prior art; (2) any differences between the claimed subject matter and the
prior art; (3) the level of ordinary skill in the art; and (4) objective evidence
of nonobviousness, i.e., secondary considerations.10 See Graham v. John
Deere Co., 383 U.S. 1, 17–18 (1966). The level of ordinary skill in the art
may be reflected by the prior art of record. See Okajima v. Bourdeau, 261
F.3d 1350, 1355 (Fed. Cir. 2001).
B. Claim Construction
In an inter partes review based on a petition filed prior to November
13, 2018, the Board interprets claim terms in an unexpired patent according
to their broadest reasonable construction in light of the specification of the

10 The record does not contain evidence or argument regarding objective
evidence of non-obviousness.
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patent in which they appear. 37 C.F.R. § 42.100(b) (2016).11 Under that
standard, we interpret claim terms using “the broadest reasonable meaning
of the words in their ordinary usage as they would be understood by one of
ordinary skill in the art, taking into account whatever enlightenment by way
of definitions or otherwise that may be afforded by the written description
contained in the applicant’s specification.” In re Morris, 127 F.3d 1048,
1054 (Fed. Cir. 1997). Only those terms which are in controversy need to be
construed and only to the extent necessary to resolve the controversy. See
Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co., 868 F.3d 1013,
1017 (Fed. Cir. 2017); see also U.S. Surgical Corp. v. Ethicon, Inc., 103
F.3d 1554, 1568 (Fed. Cir. 1997) (holding claim construction is not
necessary when it is not “directed to, or has been shown reasonably to affect,
the determination of obviousness”).
In its Petition, Argentum proffered constructions for four claim terms:
“pancreatic neuroendocrine tumor,” “advanced tumors,” “unit dose,” and
“islet cell tumor.” Pet. 18–21. Novartis’s Preliminary Response addressed
only the construction of “advanced tumors,” agreeing that the term should be
construed to refer to a tumor that is unresectable or metastatic. Prelim.
Resp. 7–8. Novartis also asked that we state that “advanced” does not mean
“after failure of cytotoxic chemotherapy,” though this is not a construction
any petitioner asserted. Id. at 9–11.

11 An amendment to this rule does not apply here because the Petition was
filed prior to November 13, 2018. See Changes to the Claim Construction
Standard for Interpreting Claims in Trial Proceedings Before the Patent Trial
and Appeal Board, 83 Fed. Reg. 51340 (Oct. 11, 2018) (amending 37 C.F.R.
§ 42.100(b) effective November 13, 2018) (now codified at 37 C.F.R.
§ 42.100(b) (2019)).
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In our Institution Decision, we agreed with the parties that the
broadest reasonable interpretation of “advanced” tumors, when viewed in
light of the ’224 patent specification, is “metastatic or unresectable.” Dec. 6.
But we declined to incorporate in our construction a requirement that
“advanced” does not means “after failure of cytotoxic chemotherapy,” as
Novartis requested. Id. We did not consider it necessary to construe any
other terms from the challenged claims. During the instituted trial, neither
party asked that we revisit the construction of “advanced,” or argued that we
should render any further constructions. In view of the complete record, we
reaffirm our prior construction of “advanced tumor,” and do not consider
further constructions of any claim term to be necessary.
C. Obviousness over Öberg 2004, Boulay 2004, and O’Donnell
Argentum contends that claims 1–3 are unpatentable under 35 U.S.C.
§ 103(a) as having been obvious over the combined teachings of Öberg
2004, Boulay 2004, and O’Donnell. Pet. 40–47. Argentum relies upon the
Declaration of Mark J. Ratain, M.D. (Ex. 1003) to support its positions.
1. The Prior Art
Öberg 2004 discusses methods of treatment for neuroendocrine
tumors of the gastrointestinal tract and pancreas. Ex. 1027, 57. Öberg 2004
specifically discusses treatment of metastatic tumors, which Dr. Ratain
testifies would fall within the skilled artisan’s understanding of advanced
tumors. Id.; see also Ex. 1003 ¶ 101. Included in Öberg 2004 is the
following figure, which discloses an algorithm for the therapy of
neuroendocrine tumors:
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Figure 1 of Öberg 2004, shown above, discloses an algorithm for
therapy of neuroendocrine (NE) tumors beginning with surgery,
radiotherapy, or embolization as a first therapy, followed by (in the case of
high-proliferative tumors) cytotoxic therapy and, after failure of cytotoxic
therapy, experimental therapies such as rapamycin. Ex. 1027, 60. Öberg
2004 discusses rapamycin as an “interesting new compound” and suggests
clinical trials with rapamycin as a single agent or in combination with
cytotoxic chemotherapy. Id. According to Argentum, “Öberg 2004 only
differs from claims 1 and 3 of the ’224 patent in that it does not explicitly
disclose the use of everolimus,” and, as to claim 2, it does not include a
specific reference to the 10 mg/day unit dose required by that claim. Pet.
31–32.
Boulay 2004 is a study of the efficacy of treatment with “rapamycin
derivative RAD001” (everolimus) in the CA20948 synergenic rat pancreatic
tumor model. Ex. 1005, 252. According to Dr. Ratain, CA20948 is a rat
tumor line used as a model for PNET in laboratory studies, and a person of
ordinary skill in the art would have recognized that activity in the model
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would support clinical development to treat human PNETs. Ex. 1003 ¶ 112.
Boulay 2004 also notes that everolimus was a rapamycin derivative being
clinically developed at that time, for use in treatment of human cancer.
Ex. 1005, 252. Boulay concludes that everolimus “displays significant
antitumor activity in the synergenic CA20948 rat pancreatic tumor model,”
and is “well tolerated, with no significant body weight loss or mortalities
observed.” Id. at 253–54.
O’Donnell is the abstract of a poster presented at the 2003 Annual
Meeting of the American Society of Clinical Oncology, describing a phase I
study of everolimus. Ex. 1029, 200. The study was a dose escalation study,
performed “to identify the optimal biologically effective dose based on
toxicity” in patients having solid tumors. Id. O’Donnell concluded that
dosages of 5, 10, 20, and 30 mg weekly were “well tolerated” with only mild
degrees of side effects. Id.
2. The Proposed Combination
Argentum contends that a person of ordinary skill in the art, seeking
to treat patients with PNET after failure of cytotoxic chemotherapy, would
have looked to Öberg 2004’s disclosure of rapamycin as an “interesting new
compound,” and would have understood these teachings to extend to other
rapamycin derivatives known to be mTOR inhibitors. Pet. 42. Dr. Ratain
testifies that, by 2005, there was a “significant body” of data on the
administration of everolimus to humans, but no reported clinical data on
rapamycin. Ex. 1003 ¶ 135. Dr. Ratain concludes that a person of ordinary
skill in the art would have had reason to administer a rapamycin derivative,
such as everolimus, with similar biological activity to rapamycin. Id.
According to Argentum, that reason would have been further strengthened
by Boulay 2004’s disclosure of everolimus’ activity in treating a rat
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pancreatic tumor model, and O’Donnell’s disclosure that administration of
everolimus to human cancer patients was effective and safe. Pet. 43–44.
Argentum also contends that this treatment would have had a reasonable
expectation of success, particularly in view of Boulay 2004’s disclosure of
the effectiveness in the rat model. Id. at 45.
With respect to the unit dosage specified in claim 2, Argentum
concedes that O’Donnell and Boulay 2004 do not specify 10 mg/day.
Pet. 46. Nevertheless, Argentum contends that determining the optimal
dosage would have required nothing more than routine experimentation, and
Novartis has not shown any particular effectiveness of 10 mg/day as
compared to other dosages. Id. at 46–47.
3. Reason to Select Everolimus
Novartis contends that the combined art fails to render the claims
obvious, because Argentum “provides no credible reason why a [person of
ordinary skill in the art] would have been motivated to select everolimus
over other prior art compounds to treat advanced PNETs after failure of
cytotoxic chemotherapy.” PO Resp. 23–24. Novartis contends that, at the
time of the invention, numerous compounds were being developed to treat
cancer generally, and many of those compounds were in more advanced
stages of clinical development than everolimus. Id. at 24. For example,
Novartis observes that small molecule tyrosine kinase inhibitors (e.g.,
gefitinib, erlotinib, SU101, sorafenib, imatinib mesylate, and sunitinib
malate), and anti-receptor antibodies (e.g., cetuximab and trastuzumab) had
reached at least Phase III clinical trials in human cancers, and sorafenib had
completed Phase II clinical trials in NETs (including advanced PNETs). Id.
(citing Ex. 2041 ¶113; Ex. 2043, 361–66; Ex. 1037, S42–S43; Ex. 2061,
1248; Ex. 2072, 2270; Ex. 2051, 7484). Novartis asserts that a person of
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ordinary skill in the art would have favored any of these various compounds
over everolimus, given the limited state of knowledge as to its efficacy at the
time. Id. at 25.
Novartis argues that unless Argentum can prove that the skilled
artisan would have selected everolimus from among the possible treatments
available, its obviousness case must fail. PO Resp. 23. To support this
proposition, Novartis cites Insite Vision Inc. v. Sandoz, Inc., 783 F.3d 853,
861 (Fed. Cir. 2015), as holding that “[i]n cases involving a new method of
treatment using a known compound, the Board should consider whether the
prior art as a whole would have motivated a [person of ordinary skill in the
art] to select the claimed compound over other prior art compounds.” PO
Resp. 23. We disagree with Novartis’ interpretation of Insite Vision.
The Federal Circuit’s decision in appeal from the related District
Court case is instructive on this point. In that case, just as in this one,
Novartis argued that claim 1 of the ’224 patent was nonobvious because the
skilled artisan would not have been motivated to select everolimus over
other prior art compounds. District Court Decision, 287 F. Supp. 3d at 527.
The District Court accepted that argument as one basis for finding that the
claims were not invalid. Id. But the Federal Circuit found this conclusion to
be in error. Federal Circuit Decision, 923 F.3d at 1059 (“[O]ur case law
does not require that a particular combination must be the preferred, or the
most desirable, combination described in the prior art in order to provide
motivation for the current invention.”) (quoting In re Fulton, 391 F.3d 1195,
1200 (Fed. Cir. 2004)). While the Federal Circuit found that such
considerations may be appropriate when evaluating a “lead compound”
obviousness challenge, the combination asserted in the District Court (and
mirrored here) does not involve such an analysis. Id. at 1060. The Federal
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Circuit concluded that the proper inquiry in cases such as the present one is
whether a person of ordinary skill in the art would have been motivated to
modify the prior art to arrive at the claimed method of treatment. Id. “This
question was answered affirmatively when the district court found that a
person of ordinary skill ‘would have been motivated to pursue everolimus as
one of several potential treatment options.’” Id.
Judged by the correct standard, the evidence leaves little doubt that a
person of ordinary skill in the art would have been motivated to pursue
everolimus as a potential treatment option for advanced PNETs after failure
of cytotoxic chemotherapy. Novartis does not seriously contend otherwise,
focusing its arguments instead on whether the motivation to pursue
everolimus was greater than the motivation to pursue other possible
treatments. Not only does Öberg 2004 discusses rapamycin as an
“interesting new compound” that suggests clinical trials with rapamycin in
combination with cytotoxic chemotherapy, it specifically provides a
treatment algorithm that shows rapamycin among the potential
“experimental therapies” following failure of cytotoxic chemotherapy.
Ex. 1027, 60, Fig 1. And O’Donnell specifically demonstrates that
administration of everolimus to human cancer patients was safe. Ex. 1029,
200. We credit Dr. Ratain’s testimony that by 2005, there was a “significant
body” of data on the administration of everolimus to humans, but no
reported clinical data on rapamycin. Ex. 1003 ¶ 135. Given the difference
in information on everolimus and rapamycin, we find that the skilled artisan
would have been motivated to pursue everolimus as an alternative to the
rapamycin disclosed in Öberg 2004.
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4. Reasonable Expectation of Success
Even if a person of ordinary skill would have had reason to pursue
everolimus, however, our inquiry does not end there. Argentum must also
prove that the skilled artisan “would have been motivated to combine the
teachings of the prior art references to achieve the claimed invention, and
that the skilled artisan would have had a reasonable expectation of success in
doing so.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1361 (Fed. Cir. 2007).
That “expectation of success need only be reasonable, not absolute.” Id. at
1364. “Whether an ordinarily skilled artisan would have reasonably
expected success . . . is measured as of the date of the invention.” Amgen
Inc. v. F. Hoffman–La Roche Ltd., 580 F.3d 1340, 1362 (Fed. Cir. 2009).
Again, review of the District Court’s decision in the related case, as
well as the Federal Circuit’s decision on appeal, is instructive.12 The District
Court found that, as of 2001, there were no clinical trials of everolimus and
that another rapamycin derivative, temsirolimus,13 had only undergone

12 We recognize that the Federal Circuit Decision applies to the ’131 patent,
and was rendered on a different factual basis than the prior art at issue before
us. For example, the critical date for the ’131 patent is approximately four
years earlier than that of the ’224 patent, requiring a different evaluation of
the state of the art. In addition, we recognize that a district court’s decision
regarding whether a patent would have been obvious is rendered under a
different standard of proof—clear and convincing evidence—than is
required here. Therefore, the court’s determination on reasonable
expectation of success is not directly determinative of our decision here.
Nevertheless, we find the court’s analysis of the caselaw, and what factual
inquiries are relevant to the question of reasonable expectation of success,
instructive.
13 Temsirolimus, also known as CCI779 or 40-(3-hydroxy-2-
(hydroxymethyl)-2-methylpropanoate)-rapamycin (Ex. 1001, 2:11–12),
differs from everolimus by the substituent groups attached to the rapamycin
backbone. Both the district court defendant and Argentum have relied on
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Phase I study. District Court Decision, 287 F. Supp. 3d at 512. The court
also noted that everolimus and temsirolimus differ in pharmacological
properties relevant to treatment (id. at 517), and that PNETs were known to
differ from carcinoids in behavior, incidence, molecular genetics, and
responses to pharmacotherapies. Id. at 519. Noting the high rate of failure
for potential cancer treatments, especially among hard-to-treat cancers like
PNET, the court found that this would have diminished any expectation that
everolimus would be effective in PNETs. Id. at 529.
Reviewing the District Court’s findings as to the ’131 patent, the
Federal Circuit affirmed. Federal Circuit Decision, 923 F.3d 1051, 1061
(Fed. Cir. 2019) (“We conclude that the district court did not clearly err in
finding that West-Ward’s asserted prior art combination . . . failed to provide
clear and convincing evidence of a reasonable expectation of success.”).
Among the District Court’s findings noted by the appeals court were the fact
that the phase I data resulted from small sample sizes and studies that were
designed to test safety, not efficacy. Id. The court also noted that the
studies in the prior art did not disclose the number of patients enrolled who
had advanced RCC, as well as the findings regarding the pharmacological
differences between temsirolimus and everolimus. Id. The court concluded
that “[t]he district court reviewed the above evidence, determined that the
molecular biology of advanced RCC was not fully understood, recognized
the limitations in the temsirolimus phase I data, and found that such data did
not provide a person of ordinary skill with a reasonable expectation of
success. . . . We hold that the district court did not err.” Id. at 1062.

clinical trials of temsirolimus as relevant to the reasonable expectation of
success in treating patients with everolimus.
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We are presented with similar facts in the case at hand. O’Donnell,
the only prior art clinical trial of everolimus presented to us, was a Phase I
trial designed to test dosages, not efficacy. Ex. 1029, 803. While Öberg
2004 does disclose the promise of rapamycin, we agree with the District
Court that at the time of the invention the mTOR pathway was insufficiently
understood, such that a person of ordinary skill in the art would not have
reasonably expected rapamycin’s “promise,” as reported in Öberg 2004, to
translate to everolimus. Ex. 1027, 60. And in regard to Boulay 2004,
Novartis argues that the record lacks sufficient evidence to support
Argentum’s contention that the CA20948 rat pancreatic tumor model
described therein was applicable to the treatment of PNETs. Ex. 1005, 253.
On this point, again we agree with the District Court. District Court
Decision, 287 F. Supp. 3d at 526 (“I find that Defendant has failed to
establish by clear and convincing evidence that CA20948 is a PNET
model.”). Upon evaluating the full record before us, we find that the
CA20948 tumor model line originated from a pancreatic adenocarcinoma,
which is distinct from a neuroendocrine tumor (NET). Ex. 2038, 197–99;
Ex. 2041 ¶¶ 132–134. We credit and rely on Dr. Kulke’s testimony that
pancreatic adenocarcinomas and PNETs were known to differ in their origin,
incidence, clinical behavior, molecular genetics, and responses to
pharmacotherapies. Ex. 2041 ¶¶ 57, 135–136.
Argentum does not dispute the distinction between CA20948 and
PNETs, but instead argues that tests performed on CA20948 would
nevertheless be understood to be applicable to PNETs. Reply 17–18.
Argentum’s primary support for this argument derives from the De Jong
reference, which discloses the use of the CA20948 pancreatic tumor line in a
study of the treatment of neuroendocrine tumors. Ex. 1010, Abstract. As
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Novartis correctly observes, however, the De Jong study involved radiation-
based treatment of tumors using radioactive somatostatin-analogues. PO
Resp. 33; Ex.1010, 356–58. Both neuroendocrine tumors and CA20948
express somatostatin receptors; it is this commonality that made CA20948
useful as a model for NETs in De Jong’s study of radiation treatment.
Ex. 2041 ¶¶ 139, 141. But just because some features of a cell line make it
useful in studies of tumors where those features are relevant, it does not
necessarily follow that the cell line is relevant to all studies of those tumors.
See Tr. 14:15–25. As Dr. Kulke credibly explains, the person of ordinary
skill in the art would not have understood from the De Jong radiation
treatment study that CA20948 could be used as a model for NETs in a
pharmacotherapy study. Ex. 2041 ¶ 143–146. For these reasons, we agree
with the District Court that Argentum has not proven CA20948 to be a
PNET model; nor is there reason to believe that a person of ordinary skill in
the art would have considered CA20948 to be applicable to studying the
treatment of PNETs with mTOR inhibitors, much less such treatment after
the failure of cytotoxic chemotherapy.
We also agree with the District Court’s evaluation of the state of the
art, and its finding that at the time of the invention “the molecular
mechanisms underlying PNETs and the mTOR pathway’s role in human
cancers were not completely understood.” District Court Decision, 287 F.
Supp. 3d at 520 (citing Ex. 2027, 317; Ex. 1033, 632–33). At the time of the
invention, no mTOR inhibitor had been approved to treat cancer in humans,
and we credit Dr. Kulke’s testimony that it was unclear whether mTOR
inhibitors would be an effective approach to cancer treatment. Ex.
2041 ¶71. Publications report that as of 2004 it was “unclear what role
mTOR kinase activity plays” (Ex. 1005, 253), and “a number of unresolved
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questions regarding the function and the mechanism of action of mTOR”
remained as of 2005 (Ex. 2027, 314, 317). Given the complexity of the cell
signaling pathways and the incomplete understanding of the activity of
mTOR inhibitors, we find that the relevant art at the time of the invention
remained highly unpredictable.
In addition to the foregoing, we also find the Federal Circuit’s recent
decision in OSI Pharmaceuticals, LLC v. Apotex Inc., 939 F.3d 1375 (Fed.
Cir. 2019), analogous to the case at hand and helpful guidance for resolution
of these issues. In OSI Pharmaceuticals, the Federal Circuit reversed the
Board’s determination that certain claims to methods for treating non-small
cell lung cancer (NSCLC) with the drug erlotinib were unpatentable as
having been obvious, concluding that substantial evidence did not support
the Board’s finding of reasonable expectation of success. 939 F.3d at 1377.
The Federal Circuit found that the Board had “misinterpreted the
asserted references to teach more than substantial evidence supports.” Id. at
1377–78. The Board had found that the prior-art reference Gibbs provided
“a clear inference” that “erlotinib has anti-cancer activity against non-small
cell lung cancer.” Id. at 1383. On review, the Court noted that Gibbs “is a
review article that collects, reviews, and analyzes other research studies.”
Id. And looking to the underlying references cited in Gibbs, the Court found
that none of those references discussed erlotinib’s effect on NSCLC. Id. at
1383–84.
The Board had also found that the combination of Gibbs with prior-art
reference Schnur, or Schnur with OSI’s Form 10-K, “would have provided a
person of ordinary skill with a reasonable expectation of success in using
erlotinib to treat NSCLC in a mammal.” Id. at 1384. The Court disagreed,
finding that once properly read, the asserted combinations of prior art “do
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not provide substantial evidence supporting the Board’s findings of
reasonable expectation of success.” Id. The Court noted that Schnur “fails
to disclose any in vitro or in vivo efficacy data for erlotinib or otherwise
suggest the use of erlotinib to treat NSCLC.” Id. The combination of Gibbs
and Schnur, the Court explained, thus at most taught only that erlotinib “has
good anticancer activity in some cancers, not including NSCLC.” Id. The
Court found “significant” the lack of efficacy data “or other indication of
success” because of (1) the “highly unpredictable nature of treating NSCLC,
which is illustrated by the over 99.5% failure rate of drugs entering Phase
II,” and (2) the undisputed fact “that a drug’s success in treating one type of
cancer does not necessarily translate to success in treating a different type of
cancer.” Id.
Given these facts, the Court concluded that:
These references provide no more than hope—and hope that a
potentially promising drug will treat a particular cancer is not
enough to create a reasonable expectation of success in a highly
unpredictable art such as this. Indeed, given a 99.5% failure rate
and no efficacy data or any other reliable indicator of success,
the only reasonable expectation at the time of the invention was
failure, not success. It is only with the benefit of hindsight that a
person of skill in the art would have had a reasonable expectation
of success in view of the asserted references.
Id.
We are presented with similar facts here. The parties do not dispute
that PNETs were understood to be a particularly fatal and difficult-to-treat
form of cancer. Ex. 1001, 3:1–10 (PNETs have 5-year patient survival rate
of 55.3%). Id. at 3:1–10. This is especially so of PNETs in patients who
have previously failed cytotoxic chemotherapy. For example, Moertel
reported that while positive response rates for first-line therapies of PNETs
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ranged from 30–69 percent, in patients where first-line therapy had failed the
second-line treatment was successful only 17% of the time, and those
responses were transient. Ex. 1023, 519. See also Ex. 2001 ¶¶ 75–77;
Ex. 2012, 518; Ex. 2011, 4767. Although Dr. Ratain points out that these
studies tested the efficacy of second-line cytotoxic therapies, not second-line
molecularly targeted therapies like mTOR inhibitors (Ex. 1119 ¶¶ 28–33),
this distinction does not change the fact that at the time of the invention, no
second-line therapy had demonstrated in clinical trials a significant chance
of success in treating advanced PNETs.
Even aside from the particular challenges to treatment posed by
PNETs, we find that oncology drugs in general were known to have a low
rate of success, with only 5% progressing from first-in-human trials to
regulatory approval, a lower rate than almost all other types of drugs. Ex.
2023, 711–12, Fig. 1. Oncology drugs were also less likely to be successful
in phase II trials than other types of drugs. Id. at 712 (“[T]he highest rate of
attrition at this phase is in the oncology field: more than 70% of oncology
compounds fail in [phase II].”). And the rate of success in trials is further
lowered for drugs that have a novel mechanism of action, such as mTOR
inhibitors at the time of the invention. Id. at 713; Ex. 2041 ¶¶ 164, 266 (“As
of November 2005, everolimus was a compound with a novel mechanism of
action . . . because no mTOR inhibitor had regulatory approval or had
published Phase III clinical trial results for the treatment of any type of
cancer.”).
Also analogous to the facts presented in OSI Pharmaceuticals is the
fact that, at the time of the invention, there was no efficacy data for the
treatment in question, or any other reliable indicator of success. As
discussed above, the only clinical trial of everolimus in the record is
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O’Donnell, which discloses a Phase I study. Ex. 1029, 200. But Phase I
trials were intended to study the toxicity of a drug, not its efficacy. Ex. 2041
¶ 160, n.17. And more broadly, there had been no pharmacotherapy at all
that had been shown to have clinical efficacy against advanced PNETs after
failure of cytotoxic chemotherapy. Ex. 1063, 79–80; Ex. 2041 ¶ 276. While
Phase II clinical trials had been conducted on temsirolimus, another mTOR
inhibitor related to everolimus, those trials concluded that temsirolimus had
“little activity” and did not warrant further evaluation in advanced NETs.
Ex. 2028, 1148, 1150–51. Although Argentum presents evidence as to the
efficacy of everolimus in treating the CA20948 rat pancreatic tumor model,
as discussed above we agree with the District Court’s finding that this is not
a PNET model and would have been of limited relevance in predicting the
efficacy of treating PNETs, especially advanced PNETs after failure of
cytotoxic chemotherapy.
In sum, the record as a whole leads us to the conclusion that, at best,
there was hope that everolimus could be successful in treating advanced
PNETs after failure of cytotoxic chemotherapy. But as the Federal Circuit
put it, “hope that a potentially promising drug will treat a particular cancer is
not enough to create a reasonable expectation of success in a highly
unpredictable art.” OSI Pharms., 939 F.3d at 1384. For these reasons, we
cannot conclude that the combined prior art or other evidence of record
proves by a preponderance of the evidence that a person of ordinary skill in
the art would have had a reasonable expectation of using everolimus to treat
advanced PNETs after failure of cytotoxic chemotherapy, as required by the
claims. And it follows that Argentum has failed to prove by a
preponderance of the evidence that claims 1–3 would have been obvious
over the combined disclosures of Öberg 2004, Boulay 2004, and O’Donnell.
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D. Obviousness over Öberg 2004, Boulay 2004, O’Donnell, and
Tabernero
Argentum also contends that, even if the dosage limitation of claim 2
is not obvious as being routine experimentation in light of Öberg 2004,
Boulay 2004, and O’Donnell, Tabernero explicitly teaches such a dosage.
Pet. 48.
Tabernero is a presentation abstract regarding a Phase I study of the
use of everolimus in patients with advanced solid tumors. Ex. 1038.
Tabernero discloses that everolimus inhibits mTOR, a protein kinase
involved in “the regulation of cell growth, proliferation, and survival.” Id.
Tabernero recommends further Phase II–III development of everolimus, at a
dosage of 10 mg daily, as a single agent tumor treatment. Id.
Our determination above, that the record does not support a finding of
reasonable expectation of success in treating advanced PNETs after failure
of cytotoxic chemotherapy by combining Öberg 2004, Boulay 2004, and
O’Donnell, also determines the outcome on this ground. First, Argentum
does not contend that Tabernero provides a reasonable expectation of
successfully treating advanced PNETs, only relying on the dosage presented
in the reference as teaching the claimed dosages. Second, as discussed
above, phase I trials such as those disclosed in Tabernero assess the
relationship between dosage and safety, not efficacy. Third, there is no
evidence that the patients in Tabernero presented with PNETs, let alone
advanced PNETs. We cannot conclude from Tabernero that there would
have been a reasonable expectation of success as to the efficacy of a dosage
of 10 mg in treating advanced PNETs after failure of cytotoxic
chemotherapy. On this point, we note that the District Court also found that
“[a]lthough Tabernero provided a [person of ordinary skill in the art] with a
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safe daily oral everolimus dose in advanced solid tumors for further
anticancer clinical development, the reported results provide no indication
that everolimus would be effective against advanced PNETs after the failure
of cytotoxic chemotherapy.” District Court Decision, 287 F. Supp. 3d at
528–29.
E. Obviousness over Boulay 2004, O’Donnell, and Duran
Argentum also contends that claims 1–3 would have been obvious
over the combined disclosures of Boulay 2004, O’Donnell, and Duran.
Pet. 49–52. The disclosures of Boulay 2004 and O’Donnell relied upon by
Argentum are set forth above.
Duran discusses the administration of the rapamycin derivative
temsirolimus to patients having metastatic neuroendocrine carcinomas
(NECs), which Dr. Ratain testifies are a subset of advanced NETs.
Ex. 1011, 3096; Ex. 1003 ¶ 129. Specifically, Duran notes islet cell
carcinomas as a subset of the treated NECs. Ex. 1011, 3096. Of the 23
patients in the study, 11 had undergone prior chemotherapy. Id. Duran
concludes that temsirolimus appears to have antitumor activity in NECs. Id.
Argentum contends that Duran teaches that temsirolimus, which is
related to everolimus, had been shown to be safe and effective as
monotherapy in patients with advanced NET previously treated with
cytotoxic chemotherapy. Pet. 49. This, combined with Boulay 2004’s
teaching that everolimus was successful in a rat pancreatic tumor model, and
O’Donnell’s disclosure that everolimus was tolerated and effective in
humans, allegedly would have led a person of ordinary skill in the art to
administer everolimus to a patient having advanced NETs after failure of
cytotoxic chemotherapy. Id. at 49–50. Relying on the testimony of
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Dr. Ratain, Argentum contends that such a treatment would have had a
reasonable expectation of success. Id. at 50 (citing Ex. 1003 ¶ 167).
With respect to claim 2, Argentum again contends that the dosage
limitation would have been the result of routine experimentation. Pet. 51–
52. As with the prior ground, Novartis does not address claim 2 separately
or contend that the proper dosage would not have been determined via
routine experimentation.
Having reviewed Duran, we cannot conclude that its addition to the
ground of unpatentability in place of Öberg 2004 remedies the problem with
the Öberg 2004, Boulay 2004, and O’Donnell ground discussed above,
namely the lack of a reasonable expectation of success in treating advanced
PNET following failure of cytotoxic chemotherapy. Duran discloses
treatment with temsirolimus, which as discussed above is pharmacologically
different than either everolimus or rapamycin. Ex. 1011, 3096; see also
District Court Decision, 287 F. Supp. 3d at 528 (noting the “clinically-
relevant differences in everolimus and temsirolimus”). We also note that
Duran reported only “interim” results, and its trial was an uncontrolled,
single-arm study. Ex. 1011, 3096 (“study accrual is ongoing”). Based on
these findings, we agree with the District Court that “[a]t most, a [person of
ordinary skill in the art] would have concluded that Duran disclosed
preliminary data supporting the notion that temsirolimus may be effective to
treat metastatic neuroendocrine carcinomas.” District Court Decision, 287
F. Supp. 3d at 528. And we note that, in a follow-up publication, Duran
noted that temsirolimus had “little activity” and “did not warrant further
single-agent evaluation.” Ex. 2028, 1148. We conclude, on this record, that
the combined disclosures of the prior art would not have provided a
reasonable expectation of success in treating advanced PNET with
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everolimus following failure of cytotoxic chemotherapy. For this reason,
Argentum’s proposed ground of unpatentability based on obviousness over
Duran, Boulay 2004, and O’Donnell fails.
F. Obviousness over Boulay 2004, O’Donnell, Duran, and Tabernero
As with the prior ground involving Öberg 2004, Argentum contends
that even if Boulay 2004, O’Donnell, and Duran do not teach or suggest
claim 2’s dosage limitation of 10 mg/day, this dosage is explicitly set forth
by Tabernero. Pet. 53. Again, Novartis does not address this ground
separately or contend that Tabernero does not disclose this dosage of
everolimus.
Our conclusion above, that a person of ordinary skill in the art would
not have had a reasonable expectation of success in achieving the method of
claim 1 based on Boulay 2004, O’Donnell, and Duran, also applies to this
ground of unpatentability. As explained above regarding Boulay 2004,
O’Donnell, and Duran, the addition of Tabernero to the combination does
not remedy the lack of a reasonable expectation of success. Argentum has
not carried its burden of proof on this ground.
G. Motion to Exclude
Novartis filed a Motion to Exclude seeking exclusion of certain
evidence filed by Argentum. First, Novartis asks us to exclude the
Declarations of Dr. Ratain (Exs. 1003, 1119) under Federal Rule of
Evidence (FRE) 702, because Dr. Ratain is allegedly not an expert in the
technology of the ’224 patent. Mot. Exclude 2–6. Second, Novartis
requests exclusion of a number of Argentum’s exhibits because they were
allegedly not relied upon in the Petition or Reply. Id. at 6–8. Third,
Novartis “provisionally” moves to exclude “any evidence that does not
appear in instituted Grounds 1–4 that [Argentum] may rely upon to establish
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any element of their prima facie case.” Id. at 8–9. Finally, Novartis asks
that, under FRE 106 we consider certain portions of Dr. Kulke’s testimony
(Exs. 1070, 1095, 1119) that were not cited by Argentum in its papers. Id. at
9–14.
Addressing Novartis’ last argument first, Argentum argues that
Novartis uses FRE 106 as a pretext to discuss various portions of
Dr. Kulke’s testimony in a “thinly veiled second sur-reply.” Opp. Exclude
2–3. According to Argentum, FRE 106 permits the introduction of
additional evidence that, in fairness, ought to be considered; it is not a basis
for excluding evidence. Id. (citing Mobile Tech, Inc. v. Invue Sec. Prods.
Inc., IPR2016-00892, Paper 35 at 68–69 (PTAB Sept. 28, 2017) (noting that
FRE 106 “provides a basis for including, rather than excluding, evidence.”).
Because the portions of Dr. Kulke’s testimony cited by Novartis are already
in the record, Argentum argues that Novartis is using its Motion as simply
an opportunity to further discuss its own expert’s testimony. Opp. Exclude
2–3.
We agree. If Argentum had submitted only certain portions of
Dr. Kulke’s testimony into the record before us, Novartis would be entitled
to rely on FRE 106 to request that the Board admit other portions of his
testimony that, in fairness, should be considered. But that is not what
Novartis requests here; nor could it, given that Exhibits 1070, 1095, and
1119 were already admitted in their entirety. And in any event, Novartis’
request would not have been proper as part of a motion to exclude. Upon
reviewing the Motion, it is clear that Novartis is using its FRE 106
arguments as a vehicle for introducing additional citations to, and discussion
of, Dr. Kulke’s testimony that were not introduced in the multiple other
opportunities for merits briefing that Novartis had during this trial. For this
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reason, we have not considered the citations to Dr. Kulke’s testimony on
pages 9–14 of the Motion.
On Novartis’ “provisional” motion to exclude “any evidence” that
does not appear in the instituted grounds, Argentum notes that Novartis has
failed to satisfy any of the requirements of a motion to exclude, such as
specifically identifying the evidence to be excluded and showing that the
moving party previously served objections to that evidence. Opp. Exclude
10–11. Novartis attempts to justify its “provisional” motion by citing to
Federal Circuit decisions such as In re NuVasive, Inc., 841 F.3d 966, 972–73
(Fed. Cir. 2016) and Genzyme Therapeutic Prods. LP v. Biomarin Pharm.
Inc., 825 F.3d 1360, 1368 (Fed. Cir. 2016) as “encourag[ing] patent owners
to move to exclude reliance on evidence outside of the instituted grounds,
lest they risk waiving objections to such misuse.” Reply Exclude 5. Even if
this is a proper interpretation of these Federal Circuit cases, however, they
do not grant Novartis the ability to circumvent our Rules by filing a vague
“provisional” motion to exclude. We deny Novartis’ Motion on this basis.
Novartis’ remaining bases for its Motion—that Dr. Ratain’s testimony
and certain exhibits not cited in the briefs should be excluded—are moot
given our determination on the merits. We have found that Argentum has
not shown by a preponderance of the evidence that claims 1–3 of the ’224
patent are unpatentable even if Dr. Ratain’s testimony and the other exhibits
are considered; excluding this evidence would not alter the result. As such,
we dismiss as moot Novartis’ Motion to Exclude on these bases.
III. CONCLUSION
Based on our review of the entirety of the record developed at trial,
Argentum has not proven by a preponderance of the evidence that any of the
challenged claims are unpatentable.
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IV. ORDER
In consideration of the foregoing, it is hereby:
ORDERED that claims 1–3 of U.S. Patent No. 9,006,224 B2 have not
been proven unpatentable;
FURTHER ORDERED that Novartis’ Motion to Exclude (Paper 35)
is denied-in-part and dismissed-in-part; and
FURTHER ORDERED that, because this Decision is final, a party to
the proceeding seeking judicial review of the Decision must comply with the
notice and service requirements of 37 C.F.R. § 90.2.

Claims

35
U.S.C. §
Reference(s)/Basis Claims
Shown
Unpatentable
Claims
Not shown
Unpatentable
1–3 103(a) Öberg 2004,
Boulay 2004,
O’Donnell
1–3
2 103(a) Öberg 2004,
Boulay 2004,
O’Donnell,
Tabernero
2
1–3 103(a) Boulay 2004,
O’Donnell, Duran
1–3
2 103(a) Boulay 2004,
O’Donnell, Duran,
Tabernero
2
Overall
Outcome
1–3
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FOR PETITIONER:
Daniel Brown
daniel.brown@lw.com

Jon Strang
jonathan.strang@lw.com

FOR PATENT OWNER:
Nicholas Kallas
nkallas@fchs.com

Raymond Mandra
rmandra@fchs.com